B.sc. III Chemistry Paper b - Govt.college for girls...

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B.sc. III Chemistry Paper B Submited by :- Dr. Sangeeta Mehtani Associate Professor Deptt. Of Chemistry PGGCG, sec11 Chd

Transcript of B.sc. III Chemistry Paper b - Govt.college for girls...

Page 1: B.sc. III Chemistry Paper b - Govt.college for girls ...cms.gcg11.ac.in/attachments/article/107/B.sc. III Chemistry Organic...Organic synthesis via Enolates 1. 2. Acidity of α-hydrogens.

B.sc. III

Chemistry

Paper B

Submited by :- Dr. Sangeeta Mehtani Associate Professor Deptt. Of Chemistry PGGCG, sec11 Chd

Page 2: B.sc. III Chemistry Paper b - Govt.college for girls ...cms.gcg11.ac.in/attachments/article/107/B.sc. III Chemistry Organic...Organic synthesis via Enolates 1. 2. Acidity of α-hydrogens.

ORGANIC SYNTHESIS VIA ENOLATES

Page 3: B.sc. III Chemistry Paper b - Govt.college for girls ...cms.gcg11.ac.in/attachments/article/107/B.sc. III Chemistry Organic...Organic synthesis via Enolates 1. 2. Acidity of α-hydrogens.

Organic synthesis via Enolates

1.

Acidity of α-hydrogens.

2.

Alkylation of diethylmalonate.

3. Synthesis of ethyl acetoacetate by Claisen condensation (with mechanism). 4.

Keto-enol tautomerism of ethyl acetoacetate.

5.

Properties and synthetic applications of aceto acetic ester.

6. Synthesis of enamines. 7. Use of enamines in alkylation and acetylation.

1. Acidity of α hydrogens:

The α (alpha) - hydrogen is the hydrogen atom that is bound to the carbon (called as α - carbon atom) adjacent to the carbonyl carbon. The next carbon is the β-carbon and the

hydrogen atoms attached to it are called as β-hydrogen atoms and so on. O

C C C

H

H

b hydrogen

a hydro Aldehydes and ketones are weak acids and have remarkably low pKa values (between 15 and

20). Hence, they may act as a Bronsted acid in an acid-base reaction with a strong base. But, aldehydes and ketones are much stronger acids than alkanes. Due to the only minor difference in electronegativity between hydrogen and carbon, C-H bonds in alkanes are

hardly polarized. Thus, hydrogens of alkanes are in fact not acidic. The pKa values of alkanes

are around 50.

a hydrogen

b hydrogen

H

O

H

a

O

H

H

H C C H

H H

H H

H C C C Ha R C C C H

H H H H

pKa=4

The acidity of α -hydrogens of aldehydes and ketones is much less than carboxylic acids, which have pKa values around 3 to 4. Reason for acidity: The α - hydrogen of carbonyl compounds is acidic, as it is connected

with the -carbon that is directly bound to the electron withdrawing carbonyl group.

O

a C C R

aH

Acid

O O - H+

C C R C C

a carbanion enolate anio

(conjugate base stabalised by resonance)

The relatively high acidity carbonyl compounds (as compared to alkanes) is explained by the resonance stabilization of the conjugate base by the carbonyl group, or, in other words, through the stabilization of the anion formed by deprotonation. This anion is called an enolate

anion.

The negative charge is mainly distributed among the α -carbon and the carbonyl oxygen, by

resonance, which leads to the stabilization of the otherwise highly, energized carbanion.

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2. Alkylation of diethylmalonate: With sodium ethoxide, it forms a sodium derivative

called as sodiomalonic ester. This reacts with compounds containing a reactive halogen atom, e.g., alkyl halides, acid chlorides, halogen-substituted esters, etc. O

H

O

O

H

O

C2H5ONa

C

C C

C OC2H5

2H5O C

2H5O

C C

C OC2H5

H

(1) C2H5ONa (2) RX

O

R

O

O

O RX

C

2H5O

C C

C OC2H5

+ NaX

C

2H5O

C C

C OC2H5

The process on repetition produces the disubstituted derivative of malonic ester.H

O

R

O

(1) C2H5ONa

O

R

O (2) R1X

C

2H5O

C C

C OC2H5

C

2H5O

C C

C O

These substituted derivatives of malonic ester can also be readily prepared in one step by

treating the ester with two equivalents of sodium ethoxide and then with two equivalents of

alkyl halide. This procedure is used only if two identical alkyl groups are to be introduced.

O H O

C2H5O C C C OC2H5

(1)2 C2H5ONa

(2)2 RX

C2H5O

O R O

C C C OC2H5

As mentioned earlier, R may be alkyl, acetyl, acyl or halogen substituted ester.

When, R= methyl group i.e. -CH3, then reaction is expressed as-

O

H

O

(1) C2H5ONa

O

H

O

(2) CH3Br

C

2H5O

C C

C OC2H5

C

2H5O

C C

C OC2H5

+

When, R= acetyl group i.e. CH3CO-, then reaction is expressed as-

O

H

O

(1) C2H5ONa

O

H

O

(2) CH3COCl C

2H5O

C C

C OC2H5

C

2H5O

C C

C OC2H5

+

3. Synthesis of ethyl acetoacetate by Claisen condensation (with mechanism): Ethyl

acetoacetate is the ethyl ester of acetoacetic acid (CH3COOH) and is widely used as a

starting material for the synthesis of a variety of ketones and acids.

It can be prepared by Claisen condensation of ethyl acetate.

The condensation of two molecules of an ester (e.g. ethyl acetate), or of two molecules of different esters, or of one molecule of an ester with one molecule of a ketone under the

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influence of sodium or sodium ethoxide, is termed Claisen condensation (1887), and is one of

the best methods for preparing beta-ketonic esters like ethyl acetoacetate.

Two molecules of ethyl acetate condense in the presence of sodium ethoxide to produce ethyl

acetoacetate. Claisen condensation may also be brought about by sodamide or tri-

phenylmethylsodium etc.

O C2H5ONa

2 H3C C OC2H5

O H O

H3C C C C OC

Mechanism: It involves following steps. It is similar to aldol condensation.

1) Dissociation of sodium ethoxide

2) Formation of α−carbanion

O

H2C C OC2H5

3) Addition step

O

O

C2H5O

H2C C OC2H5

O O H O

4) Elimination step

+

H2C C OC2H5

H3C

0C2H5

C C

C OC2H5

O

H

O

O

H

O

H3C

C C C OC2H5

H3C C C C OC2H5

+

C2H50-

H2C C OC2H5

H

0C2H5

5. Properties and synthetic applications of aceto acetic ester: On reaction with

sodium ethoxide, ethyl acetoacetate forms a sodium derivative called as

sodioacetoactic ester. This reacts with compounds containing a reactive halogen atom,

e.g., alkyl halides, acid chlorides, halogen-substituted esters, etc. However vinyl and

aryl halides do react.

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O H O

H3C C C C OC2H5

H (1) C2H5ONa

(2) RX

O R O

H3C C C C OC2H5+ NaX

C2H5ONa

H3C

RX

H3C

O H O

C C C OC2H5

O O

C C C OC2H5

The process on repetition produces the disubstituted derivative of acetoacetic ester.

O

R

O

(1) C2H5ONa

O

R

O

(2) R1X H

3C

C C

C OC2H5

H

3C

C C

C O

As mentioned earlier, R may be alkyl, acetyl, acyl or halogen substituted ester.

When, R= methyl group i.e. -CH3, then reaction is expressed as-

O

H

O

(1) C2H5ONa

O

H

O

(2) CH3Br H3C C C C OC2H5

H3C C C C OC2H5+

The process on repetition produces the dimethyl derivative of acetoacetic ester

O

H

O

(1) C2H5ONa

O

CH3

O

(2) CH3Br H3C C C C OC2H5

H3C C C C OC2H5+

When, R= acetyl group i.e. CH3CO-, then reaction is expressed as-

O

H

O

(1) C2H5ONa

O

H

O

(2) CH3COCl H3C C C C OC2H5

H3C C C C OC2H5+

Acetoacetic ester and its alkyl derivatives can undergo two types of hydrolysis with potassium hydroxide:

(a) Ketonic hydrolysis: It is so called because a ketone is the chief product. It is carried

out by boiling with dilute aqueous or ethanolic potassium hydroxide solution, e.g.,

The ketone obtained is acetone or its derivatives, and the latter always contain the group . CH3CO- Mechanism of decarboxylation:

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H R O R O

dil KOH H3C C C C OC2H5

H

O R

H3C C C H

O R O

H3C C C C OH

H

H

H3C

H3C

O O H

- CO2 R

(b) Acid hydrolysis: It is so called because an acid is the chief product, is carried out by

boiling with concentrated ethanolic potassium hydroxide solution, e.g.,

The acid obtained is acetic acid or its derivatives as the potassium salt. The free acid is

readily obtained from these salts by treatment with inorganic acids.

Mechanism of the cleavage:

O R O

H3C C C C OC2H5 + KOH

H O R O

H3C C C C OH + KOH

H

O R O

H3C C C C OK + C2H5O

H

R O C2H5OH

C2H5O + H C C OK

O R O

H3C C C C OH + K + C

H O R O

H3C C C C OK + H2O

H

O R O

H3C C C C OK

C2H5O H

R O O

C C OK+ H3C C OC2H5

Applications: These alkylation reactions followed by ketonic hydrolysis or acidic hydrolysis

are used for the synthesis of various ketones and acids.

1.Synthesis of Ketones: The formula of the ketone is written down, and provided it contains

the group, the ketone can be synthesized via acetoacetic ester as follows. The acetone nucleus

is picked out, and the alkyl groups attached to it are then introduced into acetoacetic ester one

at a time; this is followed by ketonic hydrolysis. -CO.CH3

It is usually better to introduce the larger group before the smaller (steric effect).

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O O

H3C C OC2H5

H H

1. NaOEt 2. R-X H3C

3. Aq. H+or HO-

4. D

O

R

C +CO2+C2H5OH

H H

Reaction type: Nucleophilic substitution, then ester hydrolysis & finally decarboxylation

For example, For Butanone.

CH3COCH2

CH3

R= -C

O O

H3C C OC2H5

H H For example,

For 3-methylpentan-2-one.

O O

CH3COCH CH2CH3 R= -CH3 and R1 = -C2H5

CH3

O 1. NaOEt

2. CH3Br CH3

H3C C + CO2+C2H5OH

3. Aq. H+or HO- H H 4. D

O O O O

H3C C H H

O O

C H3C C

1. NaOEt 2. CH3Br OC2H5 H3C

H3C

5. Aq. H+or HO-

6. D

OC2H5

3. NaOEt

C 4. C2H5Br C C OC2H5 H C 0C2H5

H H3C C2H5

O

CH3

H3C C C2H5+ CO2+C2H5OH

H3C

C2H5

H

3-methylpentan-2-one 2. Synthesis of fatty acids: Here, the acetic acid nucleus is picked out, and the acetoacetic

ester derivatives are subjected to acid hydrolysis. The acetoacetic ester acid synthesis is

usually confined to the preparation of straight-chain acids or branched-chain acids where the

branching occurs on the α-carbon atom. For example,

For Synthesis of n-Butyric acid

O

O

1. NaOEt

O

O

2. C2H5I

3. acid hydrolysis

H3C

C

OC2H5

C

CH3CH2 CH2C

H3C

C

OC2H5

3. Other synthesis: Sodioacetoacetic ester reacts with many other halogen compounds besides alkyl halides, and so may be used to synthesise a variety of compounds.

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(i) 1, 3-Diketones. Here, the halogen compound used is an acid chloride. As acid chlorides

react with ethanol, the reaction is not carried out in this solvent in the usual way. The reaction

is thus carried out by treating acetoacetic ester in benzene solution with magnesium and the

acid chloride.

For example synthesis of pentane-2,4-dione

O

O

O

O

1. Mg 2. CH3COCl

C

3. ketonic hydrolysis

H3C

C

OC2H5

H3C

C

OC2H5

CH3COCH2CO

(ii) Dicarboxylic acids: These may be prepared by interaction of sodioacetoacetic ester and a

halogen derivative of an ester. e.g., preparation of succinic acid from ethyl chloroacetate:

1. NaOEt CH3COCH2CO2C2H5

CH3COCHCO2C2H5 Na

2. BrCH2COOC2H5CH3COCHCO2C

CH2CO2

3. acid hydrolysis

CH2CO2C2H5

6. Synthesis of enamines: Primary amines react with aldehydes and ketones to produce

imines. For example, the reaction of acetophenone with methyl amine.

O

CH3

+H2NCH3

OH

CH 3

NHCH3

NCH3

CH3 +

In this reaction the initially formed tetrahedral intermediate, A, undergoes dehydration. The

loss of the OH group in A could be accompanied by loss of a proton from either the NH

group or the CH3 group. The former alternative is preferred because the C-N double bond is

more stable than the C-C double bond that would be produced via the latter route, i.e. the

more stable product is preferred. Also the hydrogen attached to nitrogen is more acidic as

compared to carbon and in acid catalysed dehydration, the hydrogen attached to nitrogen gets

lost.

Note that the amine has to be primary, i.e. have two hydrogen atoms attached to the nitrogen,

for the imine to form. On the other hand, reaction of a secondary amine initially follows the

same course as that of a primary amine, but now the tetrahedral intermediate, B, cannot form

an imine because the nitrogen does not have a second hydrogen atom to lose:

O

CH3

+HN(CH3)2

OH

CH 3

N(CH3)2

N(CH3)2

CH2 +

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Consequently, intermediate B undergoes dehydration to form an alkene. (Note that the

starting material must have at least one hydrogen attached to the α-carbon in order for this

reaction to occur.) But this type of alkene is special and is called as an enamine.

O +

O +

Alkylation of Enamines

H+

HN C6H6

H+

+

N C6H6

H

H+

HN C6H6

N +H2O

N

+ H2O

N + H2O

Enamines are alkylated by treating them with alkyl halide. Benzene is used as a solvent and

the water that is formed is removed by azeotropic distillation.

N

Cl

Acylation of Enamines

C6H6

D

N N

Similar to alkylation, acylation can be done using acetyl chloride. For example,

N

O Cl

C6H6

D

N N Cl

O

The alkylated and acylated enamine are hydrolyzed to get alkylated and acylated aldehyde or ketone. Thus sequence of this reactions can shown as

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N

Cl

N

O Cl

C6H6

D

C6H6

D

N H2O/H+ O

N

H2O/H+ O

O

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